Project Summary/Abstract Endometriosis is a chronic gynecology disease characterized by increased levels of inflammation and aberrant immune function that occurs when endometrial-like tissue implants outside the uterus. Women with endometriosis are at a two-fold increased risk of infertility and endometriosis diagnoses represent 20-50% of all infertility diagnoses. Recent research has suggested that women with endometriosis as well as women with infertility may be at an increased risk of cardiovascular and other chronic diseases later in life. The current approach to studying the long-term health trajectory of women with these reproductive factors, however, has been limited to registry studies of fertility treatment with short durations of follow-up and insufficient details on endometriosis. Despite a disproportionate burden in women, stroke is particularly understudied in relation to endometriosis and infertility. Moreover, very few studies have investigated the role of endometriosis in the presence and absence of infertility, which may have independent or synergistic effects. Our proposal combines extensive phenotypic data from 116,429 participants in the Nurses' Health Study II collected prospectively over 30 years of follow-up as well as biologic samples to address these gaps in the existing literature. Specifically, our proposal will address: 1) the relationship between endometriosis, infertility, and stroke (total, hemorrhagic, and ischemic stroke (Aim 1)); 2) investigate whether the relationship between endometriosis, infertility, and stroke varies by age at menopause and mode of menopausal transition (Aim 2); and 3) the biological pathways underlying the association between endometriosis, infertility, and stroke (anti-mullerian hormone [AMH], inflammation [Interleukin-6 and high sensitivity-C Reactive Protein], lipids [high-density lipoprotein, low- density lipoprotein, total cholesterol] and adipokines [leptin, adiponectin](Aim 3)).These aims represent a rigorous and efficient opportunity to investigate endometriosis and infertility as a marker of risk of stroke in women. This proposal is a first-step toward understanding the association between endometriosis, infertility, and stroke burden and the mechanisms underlying these associations, and will provide insights that shape future research into etiology, prevention, management, and treatment.